JPH07247279A - New production of lactone derivative - Google Patents

Abstract

PURPOSE:To efficiently obtain a lactone derivative under milder conditions by reaction between a hydroxycarboxylic acid, a carboxylic anhydride and a halogenoalkylsilane in the presence of a catalyst. CONSTITUTION:This lactone derivative is obtained by reaction of (A) a hydroxycarboxylic acid of formula HO-A-COOH [A is a (substituted and/or unsaturated bond-bearing) alkylene ] with (B) 90-120 (pref. 100-110)mol%, based on the component A, of a carboxylic anhydride of formula (R<1>CO)2O [R<1> is a (substituted) aryl] (pref. 4-trifluoromethylbenzoic anhydride) and (C) 1.0-1000 (pref. 10-300)mol%, based on the component A, of a halogenoalkylslane of formula (R<2>)nSiX(4-n) (R<2> is a lower alkyl; X is a halogen; (n) is 1-3) (pref. chlorotrimethylsilane) in the presence of a cationic catalyst such as titanium tetrachloride in an inert solvent such as ether at 0-50 (pref. 10-30) deg.C.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel method for producing a lactone derivative.

[0002]

2. Description of the Related Art As physiologically active substances having a lactone skeleton, many substances are known, including macrolide antibiotics such as erythromycin. The synthetic reaction of lactone compounds is an extremely important reaction in organic synthesis. Is.

Conventionally, the following methods have been generally used to synthesize lactone derivatives.

That is, (1) a ring-closing method by forming an intramolecular ester bond, (2) a ring-closing method by forming a carbon-carbon bond of a chain compound already having an ester bond, and (3) a method by ring expansion. In particular, the ring closure method (1) by forming an intramolecular ester bond is the method that has made the most remarkable progress in recent years.

However, physiologically active substances having a lactone skeleton often have various functional groups together, and a simpler and more efficient lactone synthesis method under milder conditions is desired from the viewpoint of pharmaceutical synthesis.

Further, the present inventors have previously mentioned that when a lactone derivative is produced from a silyloxycarboxylic acid silyl ester derivative, the compound represented by the general formula (2) (R ¹ CO) ₂ O (2) (wherein R ¹ is A method for producing a lactone derivative has been developed, which comprises the presence of a carboxylic acid anhydride represented by an aryl group which may have a substituent) and a catalytic amount of a cationic catalyst (Japanese Patent Application Laid-Open No. HEI-HEI-1). 5-213922
issue).

[0007]

An object of the present invention is to provide a method for efficiently producing a lactone derivative from hydroxycarboxylic acid under milder conditions.

[0008]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have shown that when a lactone derivative is produced from a hydroxycarboxylic acid, it is represented by the general formula (2). The present invention has been completed by finding that a lactone derivative can be efficiently produced under mild conditions by allowing a carboxylic acid anhydride and a specific halogenoalkylsilane to coexist with a catalytic amount of a cationic catalyst.

That is, the present invention relates to the general formula (1) HO-A-COOH (1) (wherein A may have a substituent or an unsaturated bond). Group) and a general formula (2) (R ¹ CO) ₂ O (2) (wherein R ¹ represents an aryl group which may have a substituent). And a general formula (3) (R ² ) _n SiX _(4-n) (3) (wherein R ² represents a lower alkyl group, X represents a halogen atom, and n represents 1 to 3). A halogenoalkylsilane represented by the formula (4) in the presence of a catalytic amount of a cationic catalyst.

[0010]

[Chemical 2]

The present invention relates to a method for producing a lactone derivative represented by the formula (A is the same as defined above).

A in the general formula (1) representing the hydroxycarboxylic acid that is the starting material of the method of the present invention is an alkylene group which may have a substituent or may have an unsaturated bond. However, basically any substituent may be used, and lactonization is possible by the method of the present invention even if it has a substituent that is generally difficult to lactonize. R ¹ of the general formula (2) of the carboxylic acid anhydride to be coexisted in the reaction of the method of the present invention is preferably an aryl group having an electron-withdrawing group, particularly a halogen atom such as a fluorine atom or a chlorine atom, a trichloromethyl group, a trichloromethyl group, A phenyl group substituted with a halogen-substituted lower alkyl group such as a fluoromethyl group is preferable. As the carboxylic acid anhydride of the general formula (2), 4-trifluoromethylbenzoic acid anhydride is most preferable in terms of reaction yield. The addition amount of the carboxylic acid anhydride of the general formula (2) is 90 to 120 mol%, preferably 1 to the hydroxycarboxylic acid of the general formula (1) which is a substrate.
It is from 00 to 110 mol%.

In the method of the present invention, R ² of the general formula (3) coexisted with the carboxylic acid anhydride of the general formula (2) is a lower alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, t-. A butyl group and the like are preferable, and X is preferably a halogen atom, for example, fluorine, chlorine, bromine, iodine and the like. As the halogenoalkylsilane of the general formula (3),
Chlorotrimethylsilane is most preferred in terms of price and versatility. The addition amount of the compound of the general formula (3) is preferably 1.0 to 1000 mol%, and more preferably 10 to 300 mol% with respect to the compound of the general formula (1) as a substrate. If it is less than 1.0 mol%, a sufficient effect cannot be obtained, and 1
Even if it is added in an amount of more than 000 mol%, the yield does not change and only the production cost increases.

The cationic catalyst used in the method of the present invention includes various Lewis acids such as titanium tetrachloride, hafnium chloride, zirconium chloride, aluminum chloride, gallium chloride, indium chloride, iron chloride and tin (II) chloride, or perchlorine. Acid salts, complex salts of silver salts such as silver trifluoromethanesulfonate and various Lewis acids, and tin (II) trifluoromethanesulfonate are preferable, and 0.01 of the hydroxycarboxylic acid of the general formula (1) as a substrate is preferable. It is preferable to use -100 mol%. If it is less than 0.01 mol%, a sufficient catalytic effect cannot be obtained, and if it is added in excess of 100 mol%, the catalytic effect does not change and the production cost only increases.

The method of the present invention is carried out in a solvent which does not participate in the reaction, such as acetonitrile, ether, 1,2-dichloroethane, benzene, toluene and dichloromethane, 0 to 50.
C., preferably 10 to 30.degree. C.

[0016]

EXAMPLES The usefulness of the method of the present invention is shown below, but the present invention is not limited to the examples.

Example 1 Preparation of octadecane-12-olide

[0018]

[Chemical 3]

TiCl ₂ (OTf) under argon flow
₂ (10.8 mg, 0.026 mmol) and chlorotrimethylsilane (0.2 ml, 1.57 mmol)
Suspended in 20 ml dichloromethane and 12- under reflux.
Hydroxy octadecanoic acid (157.6 mg, 0.52
4 mmol) and 4-trifluoromethylbenzoic anhydride (209.5 mg, 0.578 mmol) in 40 ml of dichloromethane were slowly added (5 hours). A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography to obtain the desired product, octadecane-
12-Olide (135.1 mg, yield 91%) was obtained.

NMR (CDCl ₃ , TMS standard) δP
PM: 4.91 (1H, m, J = 6, 6Hz), 2.4
9-2.20 (2H, m), 1.87-1.27 (28
H, m), 0.87 (3H, t, J = 6.6 Hz) Ma
ss 282 (M +).

Examples 2 to 6 and Comparative Example 1 According to Example 1, the amount of the compound represented by the general formula (3) (chlorotrimethylsilane) added and the compound represented by the general formula (2) were changed. The reaction was carried out. The results are shown in Table 1.

[0022]

[Table 1]

Examples 7 to 13 According to Example 1, the reaction was carried out by changing the hydroxycarboxylic acid represented by the general formula (1). The results are shown in Table 2.

[0024]

[Table 2]

Examples 14 and 15 According to Example 1, ricinoleic acid lactone was produced from ricinoleic acid. The results are shown in Table 3.

[0026]

[Table 3]

Examples 16 and 17 According to Example 1, ricinoleic acid lactone was produced from ricinoleic acid. The results are shown in Table 4.

[0028]

[Table 4]

[0029]

Industrial Applicability As described above, according to the method of the present invention, it is possible to produce a lactone derivative from hydroxycarboxylic acid in a high yield under mild conditions. Since this synthetic method has the advantages of being extremely simple and efficient, it is considered to be a useful method in synthetic organic chemistry.

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Claims (3)

[Claims] 1. General formula (1) HO-A-COOH (1) (In the formula, A represents an alkylene group which may have a substituent or may have an unsaturated bond.) And a carboxylic acid represented by the general formula (2) (R ¹ CO) ₂ O (2) (wherein R ¹ represents an aryl group which may have a substituent). Anhydride and General Formula (3) (R ² ) _n SiX _(4-n) (3) (In the Formula, R ² represents a lower alkyl group, X represents a halogen atom, and n represents an integer of 1 to 3. ) Is reacted with a halogenoalkylsilane represented by the formula (1) in the presence of a catalytic amount of a cationic catalyst. (In the formula, A is the same as the above definition) A method for producing a lactone derivative. 2. The method for producing a lactone derivative according to claim 1, wherein the compound represented by the general formula (2) is 4-trifluoromethylbenzoic anhydride. 3. The method for producing a lactone derivative according to claim 1, wherein the compound represented by the general formula (3) is chlorotrimethylsilane.